Cardiovascular disease (CVD) due to atherosclerosis is the major cause of death on the US. Monocyte-macrophage (MM)-derived, lipid-filled "foam cells" are hallmarks of both early fatty streak and later, rupture-prone, thrombogenic lesions. Elevated plasma triglycerides [hyper (H) TG, fasting or post-prandial] are emerging risk factors for atherothrombotic disease; the mechanistic links are not known. One potential mechanism is via a MM receptor (R) we identified that binds apoB of TG-rich lipoproteins (TGRLP), including apoB-48 of chylomicrons (CM), inducing foam cells in vitro like those in vivo in atherosclerotic lesions and in the bone marrow, skin, and spleen in humans with persistent CMs and remnants. We have cloned the human R's cDNA (3773 bp). It encodes a new, unique R that induces TGRLP uptake and foam cell formation when transfected into R- negative CHO-K1 cells. Its approximately 3.8 kb mRNA is expressed in THP-1 monocytes, placenta, peripheral mononuclear leukocytes, bone marrow, spleen, tonsil, lymph node, and appendix, a distribution like that of foam cells in vivo in humans with persistent CMs. Immunohistochemical studies show R expression in foam cells of human aortic fatty streaks, advanced coronary and carotid lesions and MM of immune tissues. We hypothesize that the receptor's normal role is to ensure efficient delivery of essential dietary lipids and lipid-soluble vitamins to monocytes and accessible macrophages of the immune system; when overwhelmed, as in states with persistent CMs, it is involved in foam cell formation and atherogenesis. To test this hypothesis in vivo, homologous recombination in murine embryonic stem (ES) cells will be used to make R deficient (R-/- and R-/+) mice and tissue specific, over-expressing transgenics. Effects of gene dosage on lipoprotein profiles and atherosclerosis susceptibility in these and in crosses with murine models of atherosclerosis (apoE-/-, LDLR-/-) and HTG (apoCIII, and apoCI transgenics) will help clarify this R's role in lipoprotein metabolism and atherogenesis in vivo. Studies in vitro in monocytes and transfected CHOs will define mechanisms of the R's synthesis, processing, cycling, and uptake of core lipids. The potential impact of this R on CVD warrants the proposed studies to provide cellular, molecular, and in vivo functional rationales for therapeutic interventions.